Metabolic Features of Women With Polycystic Ovary Syndrome in Latin America: A Systematic Review

Background Polycystic ovary syndrome (PCOS) is an endocrine disorder that commonly affects women of childbearing age and has been associated with metabolic and reproductive abnormalities. Only a few studies have investigated metabolic traits in women with PCOS in Latin America. Therefore, we conducted a systematic review to provide an overview of the available evidence on the metabolic profile of Latin American women with PCOS. Methods We searched PubMed, Cochrane Central Register of Controlled Trials, and Embase databases for cross-sectional, case-control, or cohort studies focusing on populations of countries in South and Central America and Mexico, published until October 31, 2019. We selected studies that reported the diagnostic criteria for PCOS. In the absence of a control group, we included studies if they reported relevant metabolic data. Results The initial search yielded 4878 records, of which 41 studies were included in the systematic review. Sample sizes ranged from 10 to 288 in PCOS groups and from 10 to 1500 in control groups. The prevalence of phenotypes A and B (classic PCOS) ranged from 65.8% to 87.5% as reported in studies from Argentina, Brazil, and Chile. Metabolic syndrome ranged from 33.3% to 44.0% for phenotype A, from 15.0% to 58.0% for phenotype B, from 11.9% to 36.0% for phenotype C, and from 14.2% to 66.0% for phenotype D. Women with PCOS had higher body mass index, waist circumference, blood pressure, glucose, and homeostasis model assessment index as well as a more adverse lipid profile than those without PCOS. Conclusions Evidence from the present systematic review suggests that anthropometric and metabolic profiles are worse in women with PCOS who live in different Latin American countries than in women without PCOS living in the same region. Additional studies assessing metabolic comorbidities, such as diabetes, and distinct PCOS phenotypes in different Latin American countries are warranted and may produce invaluable information for primary and secondary prevention of PCOS in the region. This systematic review was registered with PROSPERO under number CRD42016038537. Systematic Review Registration PROSPERO, identifier CRD42016038537.


INTRODUCTION
Polycystic ovary syndrome (PCOS) is an endocrine condition that commonly affects women of childbearing age. The etiology of PCOS is uncertain, but the available evidence strongly suggests that its onset is triggered by environmental, genetic, and behavioral factors that interact in a complex manner (1)(2)(3).
Many studies have investigated the prevalence of PCOS and related metabolic abnormalities in different continents. A recent meta-analysis showed a lower prevalence of PCOS in Chinese women than in white (Caucasian), Middle Eastern (Iranian and Turkish), and black (African American and Afro-Brazilian) women (20). However, the prevalence of PCOS and metabolic profile has not yet been described in several ethnic groups, especially in Latin American populations (6,17,21,22), except for a recent meta-analysis of metabolic disturbances in Brazilian women with PCOS (23). Therefore, we conducted the present systematic review to provide an overview of the available evidence on the metabolic profile of Latin American women with PCOS, as well as the frequency of different PCOS phenotypes in this population.

Search Strategy and Study Selection
A systematic review was designed and described in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. This systematic review was registered with PROSPERO under number CRD42016038537. We searched PubMed, Cochrane Central Register of Controlled Trials, and Embase databases for cohort, case-control, crosssectional, and prevalence studies with populations of South and Central America and Mexico, published until October 31, 2019. We set no language or publication date restrictions. To identify eligible studies, we used medical subject headings (MeSH) for PubMed and Ovid Tree terms for Embase. We used the following search strategy for PubMed, with equivalent terms being used in the other databases: "Polycystic Ovary Syndrome" [MeSH] OR "Ovary Syndrome, Polycystic" OR "Syndrome, Polycystic Ovary" OR "PCOS" OR "Polycystic Ovarian Syndrome" OR "Ovarian Syndrome, Polycystic" OR "Polycystic Ovary Syndrome 1" AND "Body Mass Index" [MeSH] OR "Metabolic Syndrome" OR "Glucose Intolerance" [MeSH] OR "Intolerance, Glucose" OR "Intolerances, Glucose" OR "Diabetes Mellitus, Type 2" [MeSH]. We performed additional searches in review articles and research articles focusing on PCOS.
We selected only studies that clearly defined the diagnostic criteria for PCOS and that included at least one of the following variables in the analysis: waist circumference (WC), body mass index (BMI), glucose levels, lipid profile, homeostasis model assessment of insulin resistance (HOMA-IR), blood pressure, diabetes mellitus, metabolic syndrome (MetS), PCOS prevalence, and milder PCOS phenotypes. Eligibility assessment was done by screening the titles and abstracts of all articles selected, and when abstracts did not provide the necessary information, the full text of the article was reviewed. This was performed independently, in a standardized manner, by two investigators (RBR and LBM). Disagreements between reviewers were resolved with discussion. If a consensus was not reached, a third investigator (PMS) was consulted. When articles had missing information, we contacted the authors for further information. In the case of duplicate data that had been published more than once, we opted to include the most complete study. In addition, the reference lists of all articles fulfilling the eligibility criteria were hand searched to identify other essential citations.
system" to judge the quality of the studies in three broad perspectives: selection of the study groups, comparability of the groups, and ascertainment of the outcome of interest. Each item contains a sequence of alternative questions to be answered by the investigators. Then, a star rating system allows the semiquantitative analysis of article quality. No statistical quantitative meta-analysis was performed due to study heterogeneity. Figure 1 provides a flowchart summarizing the study selection process. The initial search yielded 4878 records. Of these, 41 studies from 40 reports were included in the systematic review. All of them were observational studies: 24 cross-sectional studies, 16 case-control studies, and one cohort study. Publication years ranged from 2004 to 2019. PCOS group size ranged from 10 to 288 participants, and control group size ranged from 10 to 1500 participants. Age ranged from 20.6 to 31.1 years for women with PCOS and from 22.7 to 34.5 years for non-PCOS controls. Table 1 presents the characteristics of studies, which included populations from Argentina (n=3) (24)(25)(26), Brazil (n=27) , Chile (n=8) (26,(54)(55)(56)(57)(58)(59)(60), Venezuela (n=2) (62,63), and Mexico (n=1) (61). Most studies used the Rotterdam criteria to diagnose PCOS, except for one study conducted in Argentina (25), one in Brazil (27), and three in Chile (54,58,60), all of which used the National Institutes of Health (NIH) criteria. The two studies from Venezuela (62,63) used criteria defined by the authors. Sixteen studies had no control group for comparison (24, 26, 27, 35, 38, 39, 43-45, 47, 51, 53, 57, 59, 63), and six had BMI-matched controls without PCOS for comparison (28,29,34,40,50,55). NOS score was 7-9 in 33 studies and ≤ 6 in 7 ( Table 2).
Regarding lipid profile, 26 studies showed triglyceride levels ranging from 81 to 157.8 mg/dL (Supplementary Table 2). Triglyceride levels were higher in women with PCOS than in controls in 11 of 17 studies (25, 29-33, 37, 52, 58, 60, 62). One BMI-matched study (29) also found higher triglyceride levels in the PCOS group. Whereas Brazilian and Argentinian studies showed mean triglyceride levels within the reference range, two studies from Chile (58,59) and one from Venezuela (62) reported mean triglyceride levels > 150 mg/dL in patients with PCOS ( Figure 4).
Low-density lipoprotein cholesterol (LDL-C) levels ranged from 88.6 to 127.3 mg/dL in women with PCOS in 24 studies. Six of 15 studies comparing data between women with PCOS and controls reported higher LDL-C levels for PCOS (28,29,40,42,52,58). LDL-C was within the reference range in control groups (Supplementary Table 2).

(Supplementary
The prevalence of PCOS was estimated in only two studies. One study was conducted in Mexico (61) with a convenience sample of 150 female Mexican volunteers aged 20 to 45 years, and the authors found a prevalence of 6.6% (95% confidence interval, 2.3%-10.9%) according to the Rotterdam criteria. The other study was conducted in the city of Salvador, Brazil (36), and estimated a prevalence of 8.5% using the Rotterdam criteria in a probability sample of 859 women aged 18 to 45 years.
Six studies reported prevalence data on PCOS phenotypes and on MetS stratified by phenotype (26,31,33,53,59) for Brazilian, Chilean, and Argentinian populations. Phenotypes A +B were more prevalent in all studies, with rates ranging from 65.8% to 87.5%. The prevalence of MetS ranged from 33.3% to

Author
Year Selection Comparability Exposure/ Outcome

DISCUSSION
PCOS is a complex disorder affecting metabolic and reproductive functions. This systematic review, which included 24 crosssectional studies, 16 case-control studies, and one cohort study conducted in Latin America, found that women with PCOS had a more adverse metabolic profile than non-PCOS controls across different countries. In most studies, BMI was within the overweight or obesity range for women with PCOS, reinforcing its contribution to the disease phenotype. In addition, MetS components, such as central obesity (measured by WC), low HDL-C, and hypertension, were prevalent in women with PCOS from different Latin American countries. Although efforts have long been made to assess the impact of different sociocultural and ethnic backgrounds on PCOS-related metabolic abnormalities, few data are available for Latin America. This region is known to have populations of different ancestry. In Brazil, pooled ancestry contributions have been listed as 0.62 European, 0.21 African, and 0.17 Amerindian (65), whereas Pacific Latin American countries are predominantly Amerindian. Argentina and Chile are particular cases that show similar European and Amerindian ancestry contributions but lower African ancestry contribution compared with Brazil (65,66). It is reasonable to assume that different genetic backgrounds may influence the phenotypic heterogeneity of PCOS, but evidence from the present systematic review rather suggests that Latin American countries are similar in terms of metabolic traits. This information may be potentially useful to public health systems in developing PCOS prevention programs and policies.
Metabolic abnormalities are considered common in women with PCOS, especially those linked to the MetS cluster, as shown in this study. However, controversy exists as to whether these features are directly related to PCOS itself or dependent on obesity-mainly on abdominal adiposity, a well-known cardiometabolic risk factor (7,67,68). In this respect, the finding of decreased insulin sensitivity in Latin American women with PCOS, as opposed to controls, is in line with current evidence from other regions (6,15) and has been associated with low-grade chronic inflammation, linked to increasing BMI (68,69). Besides, in meta-analyses of different populations, women with PCOS were more likely to have MetS (4,17,70). However, these studies provide relatively few data from Latin American populations. Insulin resistance may actually drive most of the alterations observed in PCOS, even in nonobese women. While not universally present in patients with PCOS, the presence of insulin resistance has been considered an intrinsic factor independent of obesity (71,72). Recently, we have also observed an association of insulin resistance with hypertension, regardless of BMI, in Brazilian women with PCOS, with hypertension being associated with other MetS components (18). Data from the present systematic review add support to this notion by showing that Latin American women with PCOS had higher HOMA-IR than controls in most studies.
Although patients with PCOS consistently show a more unfavorable metabolic profile than controls in different regions of the world, there are discrepancies between PCOS populations. In China, the prevalence of MetS in PCOS ranged from 18.2% in community-dwelling patients in one study (73) to 53.3% in women older than 40 years in another study (74). In a prospective cohort of 479 women with PCOS from Vietnam (Southeast Asia), patients were lean, had no increase in metabolic disease and Rotterdam phenotype D was the most prevalent (67.6%) (75). Current evidence also indicates a lower prevalence of hyperandrogenemia in women with PCOS from Asian countries (76). In Latin America, we found a predominance of Rotterdam phenotypes A and B, similar to what has been reported in most of the available studies across the world (76). A recent meta-analysis reported that, compared with controls, patients with PCOS from North America had a higher risk of MetS than those from Asia and Europe (17). Likewise, in the present systematic review, we also found a high prevalence of MetS in Latin American women with PCOS. In addition to the ethnic composition of the population, dietary habits may also influence the expression of metabolic traits in different populations. Indeed, adherence to the Mediterranean diet (77) or a low-glycemic-index diet (78) has been associated with a better metabolic profile in PCOS. Regarding the dietary pattern in Latin America, the Latin American Study of Nutrition and Health (ELANS) (79) reported low consumption of vegetables, nuts, whole grains, fish, and yogurt according to the recommendations of the World Health Organization. This may explain, at least in part, the similarities in the adverse metabolic profile between Latin American countries and other countries with high consumption of processed foods (80).
Despite the paucity of research undertaken to date, the results of the present systematic review provide a broad overview of the evidence on metabolic and anthropometric parameters in women with PCOS living in Latin American countries. The comprehensive search strategy can be seen as a strength of this study, as it covered the major electronic databases in order not to miss any relevant articles and included an active search for publications without language restrictions. Limitations include the relatively few studies found despite the vast size of the region, possible heterogeneity between studies, small sample sizes, and a lack of studies in some countries of the region, which hindered a proper comparison between women with PCOS from different Latin American countries. Nevertheless, no similar analysis has yet been undertaken. The present study is the first to provide evidence that allows us to characterize the metabolic profile of women with PCOS from an array of sociocultural and ethnic backgrounds in Latin American countries.

CONCLUSIONS
The results of the present systematic review suggest that anthropometric and metabolic profiles are worse in women with PCOS who live in different Latin American countries than in women without PCOS living in the same region. These findings are similar to those from North America but differ from the milder phenotype seen in Asia and Europe. Further studies assessing the prevalence of cardiometabolic comorbidities, such as diabetes and hypertension, in Latin The "x" axis shows the name of studies and reference numbers (refer to the text). a PCOS diagnosis according to NIH criteria; b PCOS diagnosis defined by the authors.
American countries are needed, which could positively impact the prevention and management strategies for PCOS.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTIONS
LM contributed to study design, was involved with data collection and analysis, drafted the article and final review. RR contributed to study design, was involved with data collection and analysis, drafted the article and final review. PS was involved in the conception and design of the study, data collection and analysis, drafted the article and final review. All authors contributed to the article and approved the submitted version.